Vitamin A and Human Health: What’s the Latest Research?

What is vitamin A, and where does it come from?

Vitamin A is not one single compound. Rather, it is the name given to a group of fat-soluble compounds including retinol, retinoids (metabolites of retinol) and provitamin carotenoids.

As the human body does not make vitamin A, there are two main forms that can be obtained through the diet: preformed vitamin A (retinol and retinyl esters) consumed through animal products, and provitamin A carotenoids, consumed through plant-based materials, which are converted to retinol.

Each of these various forms of vitamin A are solubilized in the intestinal lumen, absorbed and converted to retinol, which is then oxidized to retinal and retinoic acid – the two main active forms of vitamin A metabolites in the body.

Studies have demonstrated vitamin A’s importance for the healthy functioning of the immune system, vision, gene expression, reproduction, embryonic development and a wide variety of other biological processes.

However, there are still many “unknowns” surrounding vitamin A, such as how its levels are maintained throughout the body, and its role in brain health and cellular repair. Here, we highlight some of the latest advancements in vitamin A research working to address these questions.

Evidence for a vitamin A sensor within the hypothalamus

Researchers from the University of Aberdeen published evidence last year demonstrating – for the first time – a potential role for the brain in vitamin A regulation.

Vitamin A is unusual compared to other vitamins, as it is stored extensively throughout the body. This means that, unless dietary deficiency is chronic, there is always an uninterrupted supply of vitamin A to all cells. Despite it being well known that vitamin A is stored in the liver, a “fundamental unresolved question is how the vitamin A concentration in the circulation is maintained,” the researchers, led by Professor Peter McCaffery and Dr. Peter Ikhianosimhe Imoesi, said.

“Understanding the regulation of vitamin A balance in the body is important given that both deficiency and excess are detrimental to human health,” said Imoesi.

Imoesi and colleagues investigated whether the hypothalamus, a structure deep in the brain that helps to regulate bodily homeostasis, could play a role. Their research is published in Science.

Using rat models and human tissue samples, they directly administered vitamin A in the form of retinol and retinoic acid to the hypothalamus, and generated animal models where the retinol-binding protein 4 (Rbp4) gene had been knocked down. Rbp4 encodes a protein that is responsible for transporting vitamin A throughout the body.

Collectively, Imoesi and colleagues’ experiments impacted the amount of vitamin A stored in the liver, and the amount that was dispersed to other cells in the body through the blood stream. The researchers believe that this evidence suggests a vitamin A sensor system exists within the hypothalamus, which regulates how the vitamin is distributed in the body. The cells in the rat hypothalamus that may form this sensor system are also present in the human hypothalamus, suggesting this system could translate to humans.

“What we found is radically new.  No one before has even suggested that the brain may control vitamin balance in the body and this is the first study to imply a ‘vitaminostatic’ role of the hypothalamus,” Imoesi explained.

“Our results suggest that vitamin A imbalance may not be simply due to irregular intake but that an abnormality in hypothalamic function due to disease or inflammation, may lead to inadequate supply of vitamin A to the body,” said Imoesi. Diseases that impact the hypothalamus may therefore present with symptoms that are due to disordered circulating vitamin A levels. “Measurement of vitamin A levels in the blood may provide a guide to whether the hypothalamus is functioning normally,” Imoesi concluded.

Exploring the genetics of circulating vitamin A

At the University of Newcastle, Professor Murray Cairns’ research explores the molecular architecture of complex disorders. His team became interested in the potential role played by vitamin A in psychiatric conditions, such as schizophrenia, after previous research suggested that varying vitamin A levels could affect neuronal connectivity in such disorders.

In Nature Communications, Cairns and colleagues conducted the largest genome-wide association study (GWAS) of circulating retinol to date. “Our new study by William Reay and colleagues combined the summary statistics from thousands of individual genomes to find out what genetic factors regulate retinol levels in blood,” Cairns said. “We essentially matched retinol levels with variation in genes to give us a better understanding of the genes involved in retinol absorption and transport in the blood.”

Blood samples from 22,274 participants were analyzed, identifying 8 common gene variant loci associated with retinol, including genes that are not directly involved in the main retinol transport complex. “These genes were highly expressed in the liver and overrepresented amongst biological pathways including carbohydrate metabolism,” the authors described.

A phenome-wide Mendelian randomization study (MR-pheWAS) was conducted to explore causal relationships of circulating retinol with 20,000 clinical phenotypes. This data suggests that retinol could have causal effects on a wide range of biological processes, including but not limited to inflammation, the microbiome, magnetic resonance imaging-derived brain phenotypes and adiposity.

“Using this approach, we can support the significance of retinol in inflammation, plasma lipids, adiposity, vision, microbiome, brain structure/connectivity, asthma, COPD and several other traits,” Cairns explained. “This is significant because we use synthetic retinoids as drugs and potentially guide their application through a genetically informed precision medicine approach. For example, people with autoimmune diseases have low levels of retinol.”

“This work recapitulated known influences of retinol on ophthalmological measures, the innate and adaptive immune response and congenital heart malformations,” the authors said. “However, we also uncovered some less characterized relationships that may be of direct clinical relevance. We highlight forthwith the example of circulating retinol being genetically predicted to impact the thickness and surface area of several brain regions, as well as indices of brain connectivity.”

Retinoic acid is known to direct in processes such as neuronal differentiation and adult neurogenesis. It makes sense, then, that retinol could influence brain structure and connectivity throughout an individual’s life span, though its effects on the brain regions identified in this study “require further examination with respect to their clinical significance,” according to Cairns and team.  

Retinoic acid’s role in skin cells' lineage plasticity

Dr. Matthew Tierney, a postdoctoral fellow at Rockefeller University, and colleagues recently investigated how the body controls lineage plasticity, identifying an interesting role for retinoic acid. Their study is published in Science.

When we endure damage to the skin, such as a cut, graze or burn, our skin’s stem cells are quick to produce new cells and repair the epidermis. During the healing process, our body has a clever trick up its sleeve – lineage plasticity. This is when other stem cells, such as follicle stem cells, morph into epidermal stem cells to support these efforts. Hair follicles enter an intermediate state where they possess transcription factors for both hair follicle and epidermal stem cells.

“The process is necessary to redirect stem cells to parts of the tissue most in need but, if left unchecked, it can leave those same tissues vulnerable to chronic states of repair and even some types of cancer,” explained Tierney.

“Through our studies, first in vitro and then in vivo, we discovered a previously unknown function for vitamin A, a molecule that has long been known to have potent but often puzzling effects on skin and many other organs,” said Professor Elaine Fuchs, senior author of the study and Rebecca C. Lancefield Professor at Rockefeller University.

The researchers found that increasing or reducing retinoic acid levels in vivo affected how the stem cells were able to respond to injury and hair growth. High levels of retinoic acid inhibited lineage plasticity and wound repair, while lower levels promoted wound repair but limited hair regrowth.

This, said Fuchs, might explain why vitamin A’s effects on tissue biology have been so “elusive”. Topical retinoids have been found to stimulate hair growth in wounds at specific concentrations, but in excess, they also appear to prevent hair cycling.

“By defining the minimal requirements needed to form mature hair cell types from stem cells outside the body, this work has the potential to transform the way we approach the study of hair biology,” Tierney said. Understanding how to guide stem cells to make the “right” decisions could also affect cancer treatment approaches, Fuchs said: “Cancer stem cells never make the right choice – they are always doing something off-beat […] as we were studying this state in many types of stem cells, we began to realize that, when lineage plasticity goes unchecked, it’s a key contributor to cancer.”